Preparation of isonicotinic acid esters



iinited drapes atent PREPARATION oF rsonrcormrc ACID asrnns AbrahamBavley, Brooklyn, Merton G. Goliaher, New Hyde Park, and William M.McLamore, Flushing, N. Y., assignors to Chas. Pfizer & (10., inc,Brooixiyn, N. Y., a corporation of Delaware N Drawing. Application March9, 1953, Serial No. 341,345

6 Claims. (Cl. 260--295) This invention relates to an improved processfor preparing lower alkyl esters of isonicotinic acid, and moreparticularly, to an improved process for converting the lower alkylesters of 2,6-dihalopyridine-4-carboxylic acid to the correspondingisonicotinic acid esters by hydrogenolysis in the presence of apalladium catalyst.

It is known that a 2,6-dihalopyridine-4-carboxylie acid, such as2,6-dichloropyridine-4-carboxylic acid, can be reduced to isonicotinicacid by hydrogenolysis in the pres ence of a hydrogenation catalyst. Theisonicotinic acid thus prepared is readily converted to its alkyl esterswhich find application in the preparation of isonicotinic acidhydrazide, a compound useful in the treatment of tuberculosis. However,the reduction of the dichloro-acid and its subsequent conversion to anester involves certain disadvantages, among which is a costlydistillation step to remove water from the reaction mixture prior toesterification.

it has now been found that the lower alkyl esters, such as the methyl,ethyl, propyl and butyl esters, of isonicotinic acid can be prepared inexcellent yields and with a minimum of catalyst by hydrogenolysis of thecorresponding esters of 2,6-dihalopyridine-4-carboxylic acid undersuperatmospheric pressure and at an elevated temperature with the aid ofa palladium catalyst, provided that the reaction is conducted undernon-hydrolytic conditions in the presence of a base. In general, theinvention is applicable to the reduction of normal and branched chainesters wherein the alkyl group of the ester may vary from 1 to 6 carbonatoms in length and higher.

The alkyl esters of 2,6-dihalopyridine-4-carboxylic acid may be obtainedby first halogenating citrazinic acid, and then esterifying theresulting product with a lower alkanol by methods well known in the art.The methyl ester of 2,6-dichloropyridine-4-carboxylic acid is preferredfor reasons of economy.

The hydrogenolysis is carried out in an organic solvent, such as ahydrocarbon or alcohol solvent, illustrative of which are aliphatichydrocarbons such as hexane; aromatic hydrocarbons, such as benzene,xylene, toluene; aliphatic alcohols, such as methyl, ethyl, propyl,butyl alcohols and the like; and aromatic alcohols, such as benzylalcohol. When an aliphatic alcohol is employed, it is preferred toselect an alcohol corresponding to the ester undergoing reduction inorder to obviate the danger of ester interchange during reduction if asubstantially pure product is desired.

The reaction mixture is maintained substantially free from water whichcomplicates separation of the resulting products and causessaponification of the ester. The reaction is conducted in the presenceof a base which is preferably employed in an amount sufficient tomaintain the reaction mixture under alkaline conditions throughout thehydrogenolysis, thereby taking up the hydrogen halide which is split offand preventing the development of acid conditions which tend to causeover-reduction of the pyridine ring. About two equivalents of such baseper equivalent of the 2,6-dihalopyridine-4-carboxylic acid ester aregenerally adequate to accomplish this purpose, a moderate excess of thebase having no harmful efiects. Non-hydroxylic bases are employed inorder to maintain the desired non-hydrolytic condition of the reactionmixture.

A wide variety of non-hydroxylic bases are successfully employed inaccordance with the process of this invention. Thus, the bases which areuseful include primary, secondary and tertiary aliphatic amines, such asn-amyl amine, n-heptyl amine, diethylamine and triethylamine;heterocyclic amines, such as morpholine and pyridine; mixedaliphatic-aromatic amines, such as dimethylaniline; anhydrous ammonia,fused sodium acetate, and sodium methoxide. The preferred combination ofsolvent and base is that of benzene and triethylamine, since thehydrochloride of the base separates completely during the reaction, thusfacilitating purification of the product arid recovery of the base.

After the 2,6-dihalopyridine-4-carboxylic acid ester has been dissolved,the palladium catalyst is added to the solution in preparation for thehydrogenolysis. The catalyst which has been found to be particularlyeffective for the reaction is a reduced palladium supported on charcoal,which is commercially available from a number of sources. Alternatively,palladium hydroxide on charcoal may be employed and reduced in situduring hydrogenolysis. Although relatively large ratios of catalyst tothe 2,6-dihalopyridine-4-carboxylic acid can be employed successfully,it has been found that excellent yields can be obtained with as littlepalladium catalyst as 1.5 percent by weight of the2,6-dihaiopyridine-4-carboxylic acid ester, when using approximately 2equivalents of alkaline material per equivalent of ester. Use of morethan 5 percent of palladium is usually impractical, since noproportionate improvement in reaction efficiency is thereby achieved.

The hydrogenolysis is preferably carried out within the temperaturerange of 50 to 60 C. and at a pressure from 15 to 40 pounds of hydrogenper square inch, although both temperature and pressure may be variedconsiderably above and below these ranges. The time of reaction may alsovary considerably, depending upon the reaction conditions, etc., but ingeneral, from about 1 to 3 hours is suflicient to complete the desiredconversion under the conditions specified. The reaction is terminatedwhen approximately 2 mols of hydrogen have been reacted per mol of the2,6-dihalopyridine-4-carboxylic acid ester. Care should be taken toavoid extreme conditions, since saturation of the ring might occur.

Upon completion of the hydrogenolysis, the catalyst and insolubleby-products of the reaction are filtered off, and the filtrate can betreated by known methods to obtain the isonicotinic acid alkyl ester.For example, the filtrate may then be stripped of solvent, leaving acrude ester which may be purified by distillation directly or afterfurther treatment, depending upon the particular solvent and baseemployed during the reaction. Alternatively, the crude ester remainingafter solvent removal may be treated with water, and then subjected tosolvent extraction with suitable solvents, such as chloroform and carbontetrachloride, prior to distillation.

The invention is further illustrated by the following examples:

Example I A mixture of 20.6 grams of the methyl ester of2,6-dichloropyridine-4-carboxylic acid, 20.2 grams triethylamine, 5grams of 5% palladium-on-charcoal and 200 ml. of methyl alcohol wascharged to a hydrogenation vessel. Hydrogen was then introduced at apressure of 40 pounds per square inch gauge, and the bomb was shaken fora period of one hour, while maintaining a temperature between 50 and 60C. During this period the pressure dropped to 22 pounds per square inchgauge, indicating a hydrogen uptake of about 2 mols of hydrogen per molof ester. After removal of the catalyst by filtration, the filtrate wasstripped of methyl alcohol under vacuum. Water was then added, andthereafter, the product was extracted with chloroform, which wassubsequently removed under vacuum. The extract was distilled to obtain11.5 grams of methyl isonicotinate in a yield of 83.7 percent.

Example II The hydrogenolysis outlined in Example I was repeated for aperiod of A of an hour, using 1 gram of the palladium catalyst in lieuof the grams employed in accordance with Example I. After extractionwith chloroform and distillation of the ester as indicated in Example I,11.1 grams of methyl ester were recovered. The yield was 81 percent.

Example 111 Another hydrogenolysis under the same conditions with 2grams of catalyst resulted in an identical yield of 11.1 grams of ester,equivalent to the 81 percent yield above indicated. 7

Example IV A mixture of 20.6 grams of methyl ester of2,6-dichloropyridine-4-carboxylic acid, 30.3 grams of triethylamine, 1gram of 5% palladium-on-charcoal and 100 ml. of henzene was charged to ahydrogenation vessel and shaken under a hydrogen pressure of 40 poundsper square inch gauge. The temperature was maintained at about 60 C. fora period of 3 hours. The reaction mixture was then filtered to removethe catalyst and triethylarnine hydrochloride formed during thereaction. After the filtrate was stripped of benzene, the crude methylester of isonicot'mic acid was distilled for purposes of purification.The amount of ester thus obtained was 12.2 grams, amounting to anoverall yield of 89 percent.

Example V A mixture of 20.6 grams of methyl ester of2,6-dichloropyridine-4-carboxylic acid, 4 grams of anhydrous ammonia, 5grams of 5% palladium-on-charcoal, and 200 ml. of methanol was subjectedto hydrogenolysis and further treatment as in Example I. The distilledester was recovered in an amount of 8.9 grams or a 65 percent yield.

Example VI A mixture of 20.6 grams of methyl ester of2,6-dichloropyridine-4-carboxylic acid, 15.8 grams of pyridine, 5 gramsof 5% palladium-on-charcoal and 200 ml. of methanol was charged to ahydrogen vessel and subjected to an initial hydrogen pressure of 40pounds per square inch gauge. The temperature was maintained at 60 C.for a period of /2 hour, during which the pressure dropped to 24 poundsper square inch gauge. Thereafter, the catalyst was removed byfiltration and the mixture neutralized to a pH of 7.2 with'a saturatedsolution of sodium bicarbonate. After stripping oif the methanol andremoving the solids which had formed as a result thereof, water wasadded to the filtrate and the solution was acidified to a pH of 6.7 withdilute hydrochloric acid. The resulting ester was then extracted withchloroform and distilled to obtain 4.6 grams of ester in a yield of 33.8percent.

Example VII A mixture of 20.6 grams of methyl ester of2,6-dichloropyridine-4-carboxylic acid, 2.5 grams of fused sodiumacetate, 5 grams of 5% palladium-on-charcoal and 200 ml. of methanol wassubjected to hydrogenolysis for a period of 3 hours in accordance withthe procedure outlined in Example 1. After further treating the productas in Example I, 4.9 grams of ester were obtained in a yield of 40percent.

Example VIII 7 A mixture of 20.6 grams of methyl ester of2,6-dichloropyridine-'4 carboxylic acid, 17.4 grams of morpholine, 1

gram of 5% palladium-on-charcoal and 200 m1. of methanol was subjectedto hydrogenolysis as in Example I, and the purified ester thus producedwas recovered in an amount of 11.5 grams or a yield of 83.9 percent.

Example IX A mixture of 20.6 grams of methyl ester of 2,6-dichloro-Example X A mixture of 20.6 grams of methyl ester of2,6-dichloropyridine-4-carboxylic acid, 17.4 grams of n-amyl amine, 1gram of 5% palladiiun on carbon and 150 ml. of methanol was charged to ahydrogenation vessel and shaken under a hydrogen pressure of 40 poundsper square inch gauge. The temperature was maintained at about 60 forone hour. After removing the catalyst by filtration and stripping offthe methanol, cc. of water were added and the water mixture wasextracted with chloroform. The chloroform was stripped and the esterdistilled, giving 5.4 grams of ester which amounted to a yield of 39.4percent.

It is readily apparent from the above examples that this inventionprovides an economical and efiicient process for preparing the loweralkyl esters of isonicotinic acid without the disadvantages which attendprior art methods. The esters so obtained are useful as intermediates inor ganic syntheses, and, as indicated herein, they are particularlyuseful in the preparation of isonicofinic acid hydrazide, which hasshown utility in the treatment of tuberculosis.

Resort may be had to such modifications and equivalents as fall withinthe spirit of the invention and the scope of the appended claims. I

We claim:

1. A process for preparing a lower alkyl ester of isonicotinic acidwhich comprises hydrogenating a solution of a lower alkyl ester of2,6-dihalopyridine-4-carboxylic acid under non-hydrolytic conditions andunder superatmospheric pressure and at an elevated temperature, in thepresence of a palladium catalyst and a non-hydrolytic base, andterminating the reaction when approximately two mols of hydrogen havebeen reacted per mol of said 2,6-dihalopyridine-4-carboxylic acid ester.

2. A process for preparing a lower alkyl ester of isonicotinic acidwhich comprises hydrogenating a lower alkyl ester of2,6-dihalopyridine-4-carboxylic acid in an organic solvent undernon-hydrolytic conditions and superatmospheric pressure and at anelevated temperature, in the presence of a palladium catalyst and abouttwo equivalents of a non-hydroxylic base per equivalent of2,6-dihalopyridine-4-carboxylic acid ester, and terminating the reactionwhen approximately two mols of hydrogen have been reacted per mol ofsaid 2,6-dihalopyridine-4-carboxylic acid ester. a

3. A process for preparing a lower alkyl ester of isonicotinic acidwhich comprises hydrogenating a hydrocarbon solution of a lower alkylester of 2,6-dihalopyridine-4- carboxylic acid and triethylaminenon-hydrolytic and nonhydroxylic conditions and under superatmosphericpressure and at a temperature from about 50 to 60 C. in the presence ofa palladium catalyst, and terminating the reaction when approximatelytwo mols of hydrogen have been reacted per mol of said2,6-dihalopyridine-4-carboxylic acid ester.

4. A process for preparing a lower alkyl ester of isonicotinic acidwhich comprises hydrogenating an alcohol solution of a lower alkyl esterof 2,6-dichloropyridine-4- carboxylic acid and anhydrous ammonianon-hydrolytic and non-hydroxylic cond ions and under superatmosphericpressure and at a temperature from about 50 to 60 C. in the presence ofa palladium catalyst, and terminating the reaction when approximatelytwo mols of hydrogen have been reacted per mol of said2,6-dichloropyridine-4-carboxylic acid ester.

5. A process for preparing a lower alkyl ester of isonicotinic acidwhich comprises hydrogenating an alcohol solution of a lower alkyl esterof 2,6-dichloropyridine-4- carboxylic acid and morpholine non-hydrolyticand nonhydroxylic conditions and under superatmospheric pressure and ata temperature from about 50 to 60 C. in the presence of a palladiumcatalyst, and terminating the reaction when approximately two mols ofhydrogen have been reacted per mol of said2,6-dichloropyridine-4-carboxylic acid ester.

6. A process for preparing the methyl ester of isonicotinic acid whichcomprises hydrogenating a solution of 2,6dichloropyridine-4-carboxylicacid methyl ester and triethylamine in benzene non-hydrolytic andnon-hydroxylic conditions and at a pressure from about to pounds persquare inch and at a temperature from about to C. in the presence or" apalladium catalyst on charcoal, and terminating the reaction whenapproximately two mols of hydrogen have been reacted per mol of said2,6-dichloropyridinei-carboxylic acid methyl ester.

References Cited in the file of this patent Adkins: Reactions ofHydrogen (Wisconsin), pp. -23 (1946).

Wibaut: Rec. trav. Chim., vol. 63, pp. 141-6 (1944), Abstracted Chem.Abst., vol. 40, col. 4062 1946).

1. A PROCESS FOR PREPARING A LOWER ALKYL ESTER OF ISONICOTINIC ACIDWHICH COMPRISES HYDROGENATING A SOLUTION OF A LOWER ALKYL ESTER OF2,6-DIHALOPYRIDINE-4-CARBOXYLIC ACID UNDER NON-HYDROLYTIC CONDITIONS ANDUNDER SUPERATMOSPHERIC PRESSURE AND AT AN ELEVATED TEMPERATURE, IN THEPRESENCE OF A PALLADIUM CATALYST AND A NON-HYDROLYTIC BASE, ANDTERMINATING THE REACTION WHEN APPROXIMATELY TWO MOLS OF HYDROGEN HAVEBEEN REACTED PER MOL OF SAID 2,6-DIHALOPYRIDINE-4-CARBOXYLIC ACID ESTER.